USE OF TUMOR NECROSIS FACTOR INHIBITORS TOGETHER WITH ANTIVIRAL AGENTS AND THERAPEUTIC COMPOSITIONS THEREOF AGAINST HIV INFECTION

Abstract: A pharmaceutical composition comprising: (a) a tumor necrosis factor inhibitor; (b) a compound selected from the group consisting of reverse transcriptase inhibitor, protease inhibitor, a gene inhibitor, myristoylation inhibitor, cell-virus binding inhibitor, LTR promoter site inhibitor, ribosome inactivators, platelet aggregation inhibitor and prophylactic and therapeutic HIV vaccine, and (c) a pharmaceutical inert nontoxic carrier are described.

Description: USE OF TUMOR NECROSIS FACTOR INHIBITORS TOGETHER WITH ANTIVIRAL AGENTS AND THERAPEUTIC COMPOSITIONS THEREOF AGAINST HIV INFECTION The present invention relates to de novo compositions of matter for the treatment of AIDS. The present invention further relates to the de novo compositions of m& er containing TNF inhibitors and antiviral agents selected from the group of reverse transcriptase inhibitors, protease inhibitors, gene inhibitors (of such genes as gag, env, tat, rev, and pol), myristoylation inhibitors, cell-virus binding inhibitors, LTR promoter site inhibitors, ribosome inactivators, platelet aggregation inhibitors and prophylactic and therapeutic HIV vaccines. DESCRIPTION OF THE PRIOR ART Under ideal circumstances, a drug should give a patient a lasting cure, or at least improve the condition of the patient having a particular disease while causing minimal side effects. Latest advances in drug research rely on the systematic research and further understanding of the disease process at the molecular level. Over the last few years there has been an enormous amount of research directed toward Human Immunodeficiency virus (HIV), which causes Acquired Immunodeficiency Syndrome (AIDS). At the present time, the most widely accepted therapeutic composition for treating AIDS is the compound azidothymidine, also known as AZT. Recent discoveries relating to AIDS have implicated tumor necrosis factor as a stimulatory agent in the growth of HIV. Because tumor necrosis factor has been implicated as a factor in AIDS, there has been a need to look at tumor necrosis factor inhibitors of those diseases. Tumor necrosis factor inhibitors which have been studied in the past include thalidomide, pentoxifylline and xanthine derivatives. Within the context of the present specification, when applicant refers to tumor necrosis factor (TNF) it is meant to signify TNF-a, TNF -p or mixtures thereof. Antiviral therapy such as therapy for Human Immunodeficiency Virus, is the subject of vigorous research all over the world. Viruses are basically subcellular particles that can live only as intracellular parasites. They basically consist of a genome of RNA or DNA (single or double stranded), packaged inside a protein, and in some cases, with a lipid envelope covering the whole particle. Additionally, these particles infect cells, and replicate within the infected cell using much of the host cell apparatus needed to synthesize macromolecules (e.g., DNA, RNA, protein). A large number of progeny then leave the cell, often by causing it to burst. The viral progeny then infect other cells and these processes repeat over and over again. Because HIV shares many host functions for replication, the possibility of interfering with his life cycle was initially considered remote. But proteins specific to the functioning of the virus have now been identified. At the present level of research, it is possible to design molecules which interfere with these viral functions with acceptable or bearable toxic side effects. Because of the recent implications of tumor necrosis factor in the development of HIV1, it would appear desirable to combine therapeutic methods wherein a TNF inhibitor is administered to a patient with other pharmaceutical compounds such as reverse transcriptase inhibitors, gene inhibitors, and HIV protease inhibitors, myristoylation inhibitors, cell-virus binding inhibitors, LTR promoter site inhibitors, LTR promoter site inhibitors, ribosome inactivators, platelet aggregation inhibitors and prophylactic and therapeutic HIV vaccines. The prior art is silent regarding compositions of matter and uses which include tumor necrosis factor inhibitors together with anti- AIDS agents, reverse transcriptase inhibitors, HIV protease inhibitors, gene inhibitors, myristoylation inhibitors, cell-virus binding inhibitors, LTR promoter site inhibitors, LTR promoter site inhibitors, ribosome inactivators, platelet aggregation inhibitors and prophylactic and therapeutic HIV vaccines and in combined formulations therewith. SUMMARY OF THE INVENTION The primary objects of the present invention are to provide pharmaceutical compositions containing a tumor necrosis factor inhibitor and an HIV reverse transcriptase inhibitor and to administer both independently. Another object of the present invention is to provide pharmaceutical compositions containing a tumor necrosis factor inhibitor and a HIV protease inhibitor. An additional object of the present invention is to provide compositions of matter comprising a tumor necrosis factor inhibitor and an HIV gene inhibitor. Still another object of the present invention is to provide compositions of matter comprising tumor necrosis factor inhibitors and non-nucleoside reverse transcriptase inhibitors. A further object of the present invention is a method for the therapeutic treatment of HIV infections by administering concurrently a combination of a tumor necrosis factor inhibitor and one or more compounds selected from the group consisting of reverse transcriptase inhibitors, HIV protease inhibitors, gene inhibitors, myristoylation inhibitors, cell-virus binding inhibitors, LTR promoter site inhibitors, ribosome inactivators, platelet aggregation inhibitors and prophylactic and therapeutic HIV vaccines. DESCRD?TION OF THE PREFERRED EMBODIMENT The present invention deals with compositions of matter useful for therapeutic treatment of HIV and being a combination of tumor necrosis factor inhibitors and a compound selected from the group consisting of reverse transcriptase inhibitors, HIV protease inhibitors, gene inhibitors, myristoylation inhibitors, cell- virus binding inhibitors, LTR promoter site inhibitors, ribosome inactivators, platelet aggregation inhibitors and prophylactic and therapeutic HIV vaccines. The preferred compounds which are used as tumor necrosis factor inhibitors are thalidomide, pentoxifylline, and xanthine derivatives. Some of the preferred reverse transcriptase inhibitors include azidothymidine (AZT), dideoxy inosine (ddl), dideoxycytidine (ddC), fluorodideoxythymidine (FddT), as well as other compounds such as D4T, FddT 3TC, BI-RG-587, R-82150 and L697639 whose structures are shown below. D4T FddT Bl - RG - 587 L - 697639 3TC R - 82150 (& analogs: 696229, 697661) Other reverse transcriptase inhibitors include: • Lipophilic prodrug of AZT • Bis-heteroaryl/piperazine U88ZO4E Some of the preferred HIV-protease inhibitors which can be used as part of this invention are described structurally below. • KN1-227 and KNl-272-transition state mimetic tripeptides • SC52151 The preferred compounds which would act as gene inhibitors would be benzodiazepine derivatives. One promising agent which inhibits the tat gene is RO-24-7429 which is a benzodiazepine shown below. 24 - 7429 and R05 - 3335 analog (tat) Further inhibitors include: • TAR antisense transcript encoded in adeno-associated virus expression vector (tat) • Mutant HIV expression vector (rev) The preferred inhibitors of myristoylation would be: • AC2, a synthetic phospholipid The preferred inhibitors of cell-virus binding include: • EL, a synthetic amino derivative of ether phospholipids • Recombinant g l20 + MF59 adjuvant vaccine • Recombinant gpl60 + MF59/MTP-PE adjuvant vaccine • Recombinant soluble CD4 • gpl20 peptide-PPD The preferred inhibitors of LTR promoter sites would include: • Triplex-forming oligonucleotide • Strand 3B of triplex forming oligonucleotide The preferred inhibitors of platelet aggregation would include: • Dipyridamole The preferred ribosome inactivators would include: • GLQ223 -purified trichosanthin The preferred prophylactic and therapeutic HIV vaccines would be: • recombinant gpl20 + MF59 adjuvant vaccine • recombinant gpl60 + MF59/MTP-PE vaccine • recombinant gp 160 vaccine • gpl20 peptide-PPD Therapeutically, the present invention presents a method of treating HIV by combination therapy which includes administering a tumor necrosis factor inhibitor and, independently, a compound selected from the group of reverse transcriptase inhibitors, HIV protease inhibitors, gene inhibitors, myristoylation inhibitors, cell-virus binding inhibitors, LTR promoter site inhibitors, ribosome inactivators, platelet aggregation inhibitors, platelet aggregation inhibitors and prophylactic and therapeutic HIV vaccines. The following preferred examples are described below. However, they are representative without departing from the spirit of the invention or scope of the subject matter. Example 1. 200 milligrams of thalidomide are mixed with 400 milligrams of AZT. The active ingredients are triturated and Q.S. with lactose to selected capsule size. Example 2. 200 milligrams of thalidomide are mixed with 500 milligrams of ddl. The active ingredients are triturated and Q.S. with lactose to selected capsule size. Example 3. 300 milligrams of thalidomide are mixed with 500 milligrams of ddC. The active ingredients are triturated and Q.S. with lactose to selected capsule size. Example 4. 200 milligrams of pentoxifylline are mixed with 500 milligrams of AZT. The active ingredients are triturated and Q.S. with lactose to selected capsule size. Example 5. 300 milligrams of pentoxifylline are mixed with 500 milligrams of ddl. The active ingredients are triturated and Q.S. with lactose to selected capsule size. The foregoing description is offered primarily for purposes of illustration. It will be readily apparent to those skilled in the art that numerous variations in both the formulations and their method of use, not mentioned above, may be made without departing from the spirit and scope of the invention.

Claims: What is claimed is: 1. A pharmaceutical composition comprising: (a) a tumor necrosis factor inhibitor; (b) a compound selected from the group consisting of reverse transcriptase inhibitors, protease inhibitor, a gene inhibitor, myristoylation inhibitor, cell-virus binding inhibitor, LTR promoter site inhibitor, ribosome inactivator, platelet aggregation inhibitor and prophylactic and therapeutic HIV vaccine, and (c) a pharmaceutical inert nontoxic carrier. 2. The composition of claim 1 wherein said tumor necrosis factor inhibitor is selected from the group consisting of thalidomide, pentoxifylline and xan thine derivatives. 3. The composition of claim 1 wherein said reverse transcriptase inhibitor is selected from the group consisting of AZT, ddl and ddC. 4. The composition of claim 2 wherein said tumor necrosis factor inhibitor is thalidomide. 5. The composition of claim 3 wherein said reverse transcriptase inhibitor is AZT. 6. The composition of claim 1 wherein said tumor necrosis factor inhibitor is thalidomide and said reverse transcriptase inhibitor is AZT. 7. The composition of claim 1 wherein said tumor necrosis factor inhibitor is pentoxifylline and said reverse transcriptase inhibitor is AZT. 8. The composition of claim 1 wherein said TNF inhibitor is thalidomide and said reverse transcriptase inhibitor is ddl. 9. The composition of claim 1 wherein said TNF inhibitor is pentoxifylline and said reverse transcriptase inhibitor is ddl. 10. The composition of claim 2 wherein said TNF inhibitor is thalidomide and said reverse transcriptase inhibitor is ddC. 11. The composition of claim 1 wherein said TNF inhibitor is pentoxifylline and said reverse transcriptase inhibitor is ddC. 12. The composition of claim 1 wherein said TNF inhibitor is thalidomide and said gene inhibitor is the tat inhibitor RO-24-7429. 13. The composition of claim 1 wherein said TNF inhibitor is thalidomide and said myristoylation inhibitor is AC 2 . 14. The composition of claim 1 wherein said TNF inhibitor is thalidomide and said reverse transcriptase inhibitor is lipophilic prodrug of AZT. 15. The composition of claim 1 wherein said TNF inhibitor is thalidomide and said reverse transcriptase inhibitor is FddT. 16. The composition of claim 1 wherein said TNF inhibitor is thalidomide and said reverse transcriptase inhibitor is D4T. 17. The composition of claim 1 wherein said TNF inhibitor is thalidomide and said reverse transcriptase inhibitor is 3TC. 18. The composition of claim 1 wherein said TNF inhibitor is thalidomide and said reverse transcriptase inhibitor is BI-RG-587. 19. The composition of claim 1 wherein said TNF inhibitor is thalidomide and said reverse transcriptase inhibitor is R-82150. 20. The composition of claim 1 wherein said TNF inhibitor is thalidomide and said reverse transcriptase inhibitor is L697639.

Inventors: ANDRULIS PETER J JR, ANGRES ISSAC, ANDRULIS, PETER, J., JR., ANGRES, ISSAC
Applicants: ANDRULIS PHARM CORP, ANDRULIS PHARMACEUTICALS CORPORATION
Application year: 1994
Main classification: A61K31
IPC codes: A61K31